A Homeobox Gene Related to Drosophila Distal-Less Promotes Ovarian Tumorigenicity by Inducing Expression of Vascular Endothelial Growth Factor and Fibroblast Growth Factor-2

Hara, Fumikata; Samuel, Shaija; Liu, Jinsong; Rosen, Daniel; Langley, Robert R.; Naora, Honami

doi:10.2353/ajpath.2007.061025

Cited by 36 publications

(63 citation statements)

References 41 publications

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“…Previous studies have shown that DLX4 is upregulated in leukemia and lung, breast, ovarian and prostate cancers (2)(3)(4)(5). In the present study, seven paired HCC tissues were analyzed by qPCR and western blot to detect the expression status of DLX4.…”

Section: Dlx4 Is Downregulated In Hcc Tissues As Compared With the Admentioning

confidence: 88%

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Regulation of the oncogenic function of distal-less 4 by microRNA-122 in hepatocellular carcinoma

Xie

Sun

et al. 2012

Molecular Medicine Reports

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Abstract. Distal-less 4 (DLX4) is a member of the DLX family of homeobox genes. Recent reports have suggested that abnormal expression of DLX4 is present in several types of human tumors, including breast cancer, leukemia and colon cancer. However, the function and the mechanistic regulation of DLX4 in hepatocellular carcinoma (HCC) are elusive. In the present study, a proportion of hepatocellular carcinomas were identified to exhibit upregulated DLX4 expression. This study proposed that the overexpression of DLX4 is associated with the downregulation of miR-122, an underexpressed miRNA in human HCC. Functional studies have demonstrated that the downregulation of DLX4 in hepatocellular carcinoma cell lines is regulated by miR-122 through binding to its 3'UTR. Furthermore, a DLX4 overexpression vector lacking the 3'UTR was shown to abolish miR-122-induced inhibition of proliferation in the HCC cell line Hep3B. These results gave new insight into the mechanism of the miR-122/DLX4 axis in HCC.

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Section: Dlx4 Is Downregulated In Hcc Tissues As Compared With the Admentioning

confidence: 88%

“…Although absent in the majority of normal adult tissues, DLX4 has been reported to be widely expressed in leukemia and lung, breast, ovarian and prostate cancers (2)(3)(4)(5). The expression of DLX4 mRNA has been shown to be significantly increased in tumors with lymph node metastasis and a high histological grade (6).…”

Section: Introductionmentioning

confidence: 99%

Regulation of the oncogenic function of distal-less 4 by microRNA-122 in hepatocellular carcinoma

Xie

Sun

et al. 2012

Molecular Medicine Reports

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“…27 Aberrant expression of DLX family members has also been associated with breast, ovarian and lung cancer progression/invasiveness. [32][33][34] Previous studies have demonstrated that DLX1 negatively affects TGFb signaling by direct interactions with Smad4, 27 a key downstream effector of TGFb/BMP signaling. Interactions between Smads and HOX genes were also shown in other studies.…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of homeodomain genes, DLX1 and DLX2, by FLT3 signaling

Starková¹,

Gadgil²,

Qiu³

et al. 2011

Haematologica

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The onlive version of this article has a Supplementary Appendix. BackgroundActivating mutations in fms-like tyrosine kinase-3 (FLT3) are frequent in acute myeloid leukemia and represent both a poor prognostic feature and a therapeutic target. We have identified a previously unrecognized downstream effect of FLT3 activation, namely up-regulation of the homeodomain genes, DLX1 and DLX2. Design and MethodsMV4;11 cells with FLT3-internal tandem duplication mutation, RS4;11 cells with wild-type FLT3 and blasts from patients with acute myeloid leukemia were used to pursue the relation between FLT3, DLX1/2 and transforming growth factor-b (TGFb). Real-time quantitative reverse transcriptase polymerase chain reaction, western blot and reverse-phase protein array were performed to detect changes in gene and protein expression. RNA interference and MTS assays were used to study the interaction of PKC412, FLT3 inhibitor and TGFb1. ResultsA direct relationship between FLT3 activity and DLX1/2 expression was revealed by both inhibition and up-regulation of FLT3 signaling in MV4;11 and RS4;11 cell lines, respectively, in isolated blast cells from patients with acute myeloid leukemia, and in reverse-phase protein array assays of samples from patients with acute myeloid leukemia. Mechanistically, the link between FLT3 and DLX1 expression appears to involve MAPK signaling through the ERK and JNK pathways. To determine whether elevated DLX1 had a functional consequence, we explored the reported inhibition by DLX1 on TGFb/Smad signaling. Indeed, TGFb responses were blunted by FLT3 activation in a DLX1-dependent manner and FLT3 inhibition resulted in a time-dependent increase in nuclear phospho-Smad2. ConclusionsThese findings suggest that alterations in DLX1/2 contribute to the biological consequences of FLT3 activation.Key words: acute myeloid leukemia, FLT3, DLX1, DLX2, TGFb.Citation: Starkova J, Gadgil S, Hua Qiu Y, Zhang N, Hermanova I, Kornblau SM, and Drabkin HA. Up-regulation of homeodomain genes, DLX1 and DLX2, by FLT3 signaling. Haematologica 2011;96(6):820-828. doi:10.3324/haematol.2010

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“…The American Cancer Society estimates that about 22,440 women will receive a new diagnosis of ovarian cancer in the USA in 2017 [48]. In Hara's study, 47% of the ovarian carcinoma cases were found to exhibit extensive BP1 expression [47]. The data showed that BP1 expression in ovarian carcinomas is strongly associated with high tumor grade and correlates with disease stage.…”

Section: Ovarian Cancermentioning

confidence: 99%

“…In cancer, overexpression of VEGF has been shown to enhance metastasis due to angiogenesis. Overexpression of BP1 in ovarian cancer cells induces levels of VEGF and FGF-2, stimulates endothelial cell growth and leads to increased microvessel density in tumors, but it is not known whether BP1 protein directly activates FGF-2 transcription [47].…”

Section: Vascular Endothelial Growth Factormentioning

confidence: 99%

BP1, a Potential Biomarker for Breast Cancer Prognosis

et al. 2018

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Homeobox genes are critical in tumor development. An isoform protein of DLX4 called BP1 is expressed in 80% of invasive ductal breast carcinomas. BP1 overexpression is implicated in an aggressive phenotype and poor prognosis. BP1 upregulation is associated with estrogen receptor negativity so those tumors do not respond to antiestrogens. Breast cancer is the second leading cause of death in women. BP1 could serve as both a novel prognostic biomarker for breast cancer and a therapeutic target. In this review, we address the role of BP1 protein in tumorigenesis of breast cancer and four other malignancies. A number of functions of BP1 in cancer are also discussed. Female breast cancer represents 14.6% of all new cancer cases in the USA according to the National Cancer Institute [1]. An estimated 252,710 new cases of invasive breast cancer are expected to be diagnosed in women in the USA in 2017. It is also estimated that 30% of newly diagnosed cancers in women will be breast cancers [2].Breast cancer is a hormone-dependent cancer, and estrogen (17β-estradiol) plays a critical role in the initiation and the progression of this disease [3]. Estrogen, produced by the ovaries, affects the growth and function of mammary glands by binding to the estrogen receptors (ERs) α and β. Through dimerization of the receptor, translocation to the nucleus and interaction with estrogen response elements in the promoter region of targeted genes, gene expression leads to multiple biological outcomes [4]. 70% of invasive breast cancers are ER positive (ER + ), making antiestrogens essential in treating these patients [5]. Targeting the ER or its pathway using tamoxifen (a selective ER modulator) or fulvestrant (an ER downregulator) have been successful therapeutic strategies [6]. However, drug resistance remains a major challenge in treating breast cancer. The main pathway leading to resistance involves loss of ER expression or selection of an ER-negative population of cells. Moreover, these ER-negative breast cancers have a higher histologic grade and a higher proliferative rate and are associated with poorer prognosis. This highlights the key importance of finding alternative targets to treat these patients and identifying a new biomarker for breast cancer prognosis.BP1 protein, an isoform of DLX4, belongs to the homeobox gene family which includes regulatory genes implicated in early development and cell differentiation that are frequently dysregulated in cancer [7]. Therefore, targeting BP1 may provide a new avenue for breast cancer management. The first related paper was published in 1998, when the authors mapped this new homeobox gene to chromosome 17q21 and characterized its role in repression of the β-globin gene [8]. During the last 20 years, several studies have been carried out to measure BP1 levels in breast cancer and other carcinomas, with the primary aim of confirming its diagnostic and prognostic value as a biomarker. We are writing this review to consolidate and update all of the available information on BP1. Homeobox...

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A Homeobox Gene Related to Drosophila Distal-Less Promotes Ovarian Tumorigenicity by Inducing Expression of Vascular Endothelial Growth Factor and Fibroblast Growth Factor-2

Cited by 36 publications

References 41 publications

Regulation of the oncogenic function of distal-less 4 by microRNA-122 in hepatocellular carcinoma

Regulation of the oncogenic function of distal-less 4 by microRNA-122 in hepatocellular carcinoma

Up-regulation of homeodomain genes, DLX1 and DLX2, by FLT3 signaling

BP1, a Potential Biomarker for Breast Cancer Prognosis

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